TDP1 phosphorylation by CDK1 in mitosis promotes MUS81-dependent repair of trapped Top1-DNA covalent complexes.

IF 9.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY EMBO Journal Pub Date : 2024-09-01 Epub Date: 2024-07-16 DOI:10.1038/s44318-024-00169-3
Srijita Paul Chowdhuri, Benu Brata Das
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引用次数: 0

Abstract

Topoisomerase 1 (Top1) controls DNA topology, relieves DNA supercoiling during replication and transcription, and is critical for mitotic progression to the G1 phase. Tyrosyl-DNA phosphodiesterase 1 (TDP1) mediates the removal of trapped Top1-DNA covalent complexes (Top1cc). Here, we identify CDK1-dependent phosphorylation of TDP1 at residue S61 during mitosis. A TDP1 variant defective for S61 phosphorylation (TDP1-S61A) is trapped on the mitotic chromosomes, triggering DNA damage and mitotic defects. Moreover, we show that Top1cc repair in mitosis occurs via a MUS81-dependent DNA repair mechanism. Replication stress induced by camptothecin or aphidicolin leads to TDP1-S61A enrichment at common fragile sites, which over-stimulates MUS81-dependent chromatid breaks, anaphase bridges, and micronuclei, ultimately culminating in the formation of 53BP1 nuclear bodies during G1 phase. Our findings provide new insights into the cell cycle-dependent regulation of TDP1 dynamics for the repair of trapped Top1-DNA covalent complexes during mitosis that prevents genomic instability following replication stress.

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有丝分裂过程中 CDK1 磷酸化 TDP1 可促进 MUS81 依赖性修复被困的 Top1-DNA 共价复合物。
拓扑异构酶 1(Top1)控制 DNA 的拓扑结构,在复制和转录过程中缓解 DNA 的超卷曲,对于有丝分裂进入 G1 阶段至关重要。酪氨酰-DNA 磷酸二酯酶 1(TDP1)介导清除被困的 Top1-DNA 共价复合物(Top1cc)。在这里,我们发现了有丝分裂过程中 CDK1 依赖性磷酸化 TDP1 的残基 S61。S61磷酸化缺陷的TDP1变体(TDP1-S61A)被困在有丝分裂染色体上,引发DNA损伤和有丝分裂缺陷。此外,我们还发现有丝分裂中的Top1cc修复是通过依赖于MUS81的DNA修复机制进行的。喜树碱或蚜虫霉素诱导的复制应激会导致TDP1-S61A在常见脆性位点富集,从而过度刺激依赖MUS81的染色体断裂、无丝期桥和微核,最终在G1期形成53BP1核体。我们的发现为细胞周期依赖性的 TDP1 动态调控提供了新的见解,TDP1 可在有丝分裂过程中修复被困的 Top1-DNA 共价复合物,从而防止复制应激后的基因组不稳定性。
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来源期刊
EMBO Journal
EMBO Journal 生物-生化与分子生物学
CiteScore
18.90
自引率
0.90%
发文量
246
审稿时长
1.5 months
期刊介绍: The EMBO Journal has stood as EMBO's flagship publication since its inception in 1982. Renowned for its international reputation in quality and originality, the journal spans all facets of molecular biology. It serves as a platform for papers elucidating original research of broad general interest in molecular and cell biology, with a distinct focus on molecular mechanisms and physiological relevance. With a commitment to promoting articles reporting novel findings of broad biological significance, The EMBO Journal stands as a key contributor to advancing the field of molecular biology.
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